Titin Gene (TTN)

Siegfried Labeit, University of Heidelberg, Germany
Julius Bogomolovas, University of Heidelberg, Germany
Dietmar Labeit, University of Heidelberg, Germany
Henk Granzier, University of Arizona, Tucson Arizona, USA

Published online: November 2011

DOI: 10.1002/9780470015902.a0005021.pub2

The titin locus located on chromosome 2q24 in the human genome expresses about 100 kb full-length mRNAs, that are translated into giant up to 34.350-residue large polypeptides. Therefore, titin is by far the largest known protein. The titin protein is abundant in vertebrate muscles, where it spans half of the sarcomere. In situ, 1–2 m long titin polypeptides establish a sarcomeric filament system that is critical for myofibrillar integrity and elasticity. Biomechanically, titin's intrinsic elasticity is fine-tuned in the different muscle tissues through alternative splicing, post-translational modifications and protein–protein interactions. Moreover, a plethora of molecular interactions with stress-regulated ligands positions titin centrally in stretch-dependent signalling in muscle. Therefore, mutations in this filament system are important causes of hereditary cardiomyopathies and muscular dystrophies.

Key Concepts:

  • Sarcomeres consist of precisely assembled proteins that together form the basic functional units of striated muscle and give rise to efficient and finely tuned contraction.
  • In muscle tissues, 1–2 m single titin polypeptide chains span half of the sarcomere.
  • The intrasarcomeric filamentous titin protein provides sarcomeres with intrinsic elasticity and couples stretch-dependent signalling together with muscle remodelling.
  • Titin molecule is tailored to physiological requirements of different muscles through alternative splicing, post-translational modifications and protein–protein interactions.
  • Mutations in the titin gene are associated with different heart and skeletal muscle diseases.

Keywords: muscle contraction; myofibrillar elasticity and signalling; sarcomere assembly

Figure 1. (a) Schematic overview of the filament systems in vertebrate striated muscle. Centrally located thick filament (green) consisting mainly of myosin, interacts at both sides of sarcomere with thin filament (red) mainly composed of actin. Thick filament and titin are held together through multiple interactions including C-protein (red stripes). Titin extends half of the sarcomere: Its N-terminal region spans the Z-disc, and its C-terminal region the M-line, respectively. (b) Schematic model indicating titin's spring segment. The spring extends as the sarcomere is stretched and a restoring force ensues (e.g. as occurs during filling of the heart).
Figure 2. Domain architecture of soleus titin polypeptide. In addition to the 243 Ig/FN3 repeats with structural roles for Z-disc and thick filament assembly, titin also contains nonrepetitive sequence elements. Since these elements include a serine/threonine kinase domain, phosphorylation motifs and calpain protease-binding sites, titin appears to have also multiple roles in myofibrillar signal transduction. Modified from Gregorio et al. (1998) with permission from Elsevier.
Figure 3. Exon–intron structure and domain architecture of the human titin gene. Titin has a total coding mass of 4200 kDa, which is organised in 363 exons. (Figure reproduced with permission of Lippincot, Williams and Wilkins Publisher.) Numbers indicate TTN variants that are implicated in hereditary muscle diseases. The arrow on exon 37 indicates a mutation recently observed in families with arrythmogenic right ventricular failure (Taylor et al., 2011). Variants in exons 3, 14 (two different variants), 18, 49 (four different variants), 326, 335 and 358 have been associated with dilated cardiomyopathy (blue); additional variants in exons 358 and 360 have been associated with fetal cardiomyopathy (black). Mutations in titin¢s C-terminal exons 363 and 358 cause the muscular dystrophies TMD, and a severe form of diaphragm failure (for more information, see references under further reading). Modified from Bang et al. (2001) with permission from American Heart Association.
Figure 4. (a) Giant proteins in vertebrate striated muscles. On denaturing 2% polyacrylamide gels, titins bands appear as low-mobility species far above the 220 kDa myosin heavy chain (MHC), and the about 800 kDa nebulin band. Note the mobility difference between the 3700 kD titin from human soleus skeletal muscle, and the 2970 kDa titin from heart muscle (main band in mouse heart and lower titin band in human heart muscle). (b) The different titin polypeptide size classes are caused by the differential processing of titin transcripts by distinct splice pathways (Freiburg et al., 2000). Titin cDNAs from cardiac muscle (top) and soleus and psoas skeletal muscle (bottom) predict titins that have very different I-band regions. Identified splice routes are indicated by arrows, black for human and blue for rabbit. Predicted molecular weights of respective isoforms are given (right).
close
 References
    Bang ML, Centner T, Fornoff Fet al. (2001) The complete gene sequence of titin, expression of an unusual ~700 kDa titin isoform and its interaction with obscurin identify a novel Z-line to I-band linking system. Circulation Research 89: 1065–1072.
    Buyandelger B, Ng KE, Miocic S et al. (2011) Genetics of mechanosensation in the heart. Journal of Cardiovascular Translational Research 4: 238–244. Review.
    Clark KA, McElhinny AS, Beckerle MC and Gregorio CC (2002) Striated muscle cytoarchitecture: an intricate web of form and function. Annual Review of Cell and Developmental Biology 18: 637–706.
    Freiburg A, Trombitas K, Hell W et al. (2000) Series of exon-skipping events in titin's elastic spring region as the structural basis for myofibrillar elastic diversity. Circulation Research 86: 1114–1121.
    Gerull B, Gramlich M, Atherton J et al. (2002) Mutations ofTTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genetics 30: 201–204.
    Granzier H and Labeit S (2002) Cardiac titin: an adjustable multi-functional spring. Journal of Physiology 541: 335–342. Review.
    Gregorio CC, Granzier H, Sorimachi H and Labeit S (1998) Muscle assembly: a titanic achievement? Current Opinion in Cell Biology 11: 18–25.
    Hackman P, Vihola A, Haravuori H et al. (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. American Journal of Human Genetics 71: 492–500.
    Hidalgo C, Hudson B, Bogomolovas J et al. (2009) PKC phosphorylation of titin's PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circulation Research 105: 631–638, 617 p following 638.
    Itoh-Satoh M, Hayashi T, Nishi H et al. (2002) Titin mutations as the molecular basis for dilated cardiomyopathy. Biochemical Biophysical Research Communications 291: 385–393.
    Krüger M, Kötter S, Grützner A et al. (2009) Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circulation Research 104: 87–94.
    Krüger M and Linke WA (2011) The giant protein titin: a regulatory node that integrates myocyte signaling pathways. Journal of Biological Chemistry 286: 9905–9912. Review.
    Labeit S and Kolmerer B (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270: 293–296.
    Lange S, Xiang F, Yakovenko A et al. (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308: 1599–1603.
    LeWinter MM and Granzier H (2010) Cardiac titin: a multifunctional giant. Circulation 121: 2137–2145. Review.
    Taylor M, Graw S, Sinagra G et al. (2011) Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy–overlap syndromes. Circulation 124: 876–885.
    Yamasaki R, Wu Y, McNabb M et al. (2002) Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circulation Research 90: 1181–1188.
 Further Reading
    book Engel A (2004) Myology. New York: McGraw-Hill.
    book Herzog W (2000) Skeletal Muscle Mechanics: From Mechanisms to function. Chichester: Wiley.
    book Kamkin A and Kiseleva I (eds) (2010) Mechanosensitivity of the Heart. Series: Mechanosensitivity in Cells and Tissues, vol. 3. Dordrecht: Springer.
    Udd B, Vihola A, Sarparanta J, Richard I and Hackman P (2005) Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64: 636–642.

Related Sub-Topics:

Protein Structure | Cell Motility and Transport | Mutational Mechanisms of Genetic Disease | Gene and Genome Structure and Organisation | Biomolecular Interactions | Proteins: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Titin Gene (TTN)
 
How to Cite close
Labeit, Siegfried, Bogomolovas, Julius, Labeit, Dietmar, and Granzier, Henk(Nov 2011) Titin Gene (TTN). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005021.pub2]